Electron cryo-microscopy (cryo-EM), particularly single particle cryo-EM, has experienced tremendous successes in term of achievable resolution. It is now possible to determine near atomic resolution structures of a wide range of biological complexes without crystals, from as large as viruses with icosahedral symmetry, to ribosomal particles without symmetry to small integral membrane proteins such as ion channels. We have made tremendous contributions to the cryo-EM technological breakthroughs and our successes generated unprecedented high demands from many laboratories at UCSF to access cryo-EM for their NIH funded structural biology projects. The goal of this proposal is to acquire a high performance electron cryo-microscope system for efficient high-resolution data acquisition. Setting up such a high-end cryo-EM system will enable us to take full advantage of recent technological breakthroughs in single particle cryo-EM to study structures of a wide range of challenging biological macromolecules. Many biomedical research projects funded by NIH, particularly those requiring structural determination of large complexes, will benefit from availability of such a state-of-the-art cryo- EM instrument.